Mineral metabolism disorder inhibitor

Abstract

To provide a material which can prevent and improve spots by improving mineral metabolism disorder in a subepidermis, proliferating epidermis cells and normalizing epidermal turnover.SOLUTION: A mineral metabolism disorder inhibitor applied to a subepidermis of a spots portion of a skin, has, as an active ingredient, at least one kind selected from a group consisting of Rosae fructus, Scutellariae radix, olive leaf, Lonicera japonica, star fruit leaf, Centella Asiatica, rose, Artichoke, Chamomilla, Perilla frutescens, Filipendula multijuga, Paeonia lactiflora, Hamamelis, billberry leaf, Saxifraga stolonifera, indigo, ginger, Houttuynia cordata, Hypericum erectum, picea, kiwi, Lamium album, safflower, sea urchin, litchi, aloe, inositol, niacinamide, dipotassium glycyrrhizinate, orizanol, tocopherol acetate ester, and tranexamic acid.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a mineral metabolism disorder inhibitor, a TFRC1 production promoter, an ACO1 production promoter, an SLC40A1 production inhibitor, a DMT1 production promoter, and an SLC25A37 production promoter. [Background technology]

[0002] Minerals are one of the five major nutrients, along with proteins, carbohydrates, fats, and vitamins, and play important roles in the body, primarily as components of biological tissues (bones, teeth, etc.), maintaining homeostasis of body fluids (regulating pH and osmotic pressure, etc.), cofactors for enzymes, regulating the excitability of nerves, muscles, and the heart, and as components of physiologically active substances.

[0003] Minerals are broadly classified into two categories: macroelements and trace elements. Macroelements include calcium, phosphorus, potassium, sodium, sulfur, magnesium, etc. Trace elements include iron, copper, zinc, selenium, manganese, iodine, etc.

[0004] In other words, daily intake of a variety of minerals is essential for humans to maintain good health. For example, it is well known that iron deficiency causes anemia. In addition, zinc deficiency can cause skin ulcers, a weakened immune response, and hypogonadism, while copper deficiency can cause anemia and elevated plasma cholesterol levels. Conversely, excessive iron intake can cause skin pigmentation and liver damage, while excess copper can cause brain damage (Non-Patent Document 1).

[0005] There are mechanisms in the body that maintain mineral balance. For example, the sodium pump in the cell membrane consumes energy to pump sodium ions from inside the cell to the outside, maintaining a state in which there are more potassium ions inside the cell and more sodium ions outside the cell.

[0006] Naturally, mineral balance is also important for maintaining healthy skin, and it has been reported that the presence of abundant magnesium ions in the stratum corneum on the skin surface and calcium ions in the granular layer is important for skin homeostasis. It is also known that calcium ions affect the enzyme balance involved in stratum corneum desquamation (keratinization), i.e., the digestion of desmosomes.

[0007] Furthermore, trace amounts of minerals are known to be localized in the epidermis. Iron, zinc, copper, and other minerals are all necessary for various enzyme activities related to cell proliferation and antioxidant properties. Of these, iron and copper in particular are known to have narrow physiological optimum concentrations and are prone to causing oxidative damage to tissues. Abnormal localization of these minerals is thought to lead to abnormal skin turnover and oxidative pathologies (Non-Patent Document 2).

[0008] It is generally known that epidermal turnover is initiated by proliferation of basal cells and is responsible for excretion of melanin. Age spots, such as senile lentigo, are the most common type of blemish on the face and are a major cosmetic concern for many people. It has been reported that areas affected by age spots have thickened epidermis, melanin accumulation, increased expression of molecules involved in melanin production, and decreased proliferation of basal cells.

[0009] Therefore, if the reduced proliferation of epidermal cells in the skin can be activated or the expression of molecules involved in melanin production can be reduced, it is believed that the original skin functions can be restored, melanin can be excreted through epidermal turnover, and prevention, treatment, improvement, etc. of spots can be achieved.

[0010] Therefore, the present inventors focused on improving mineral metabolism in the skin as a method for improving such abnormalities in epidermal turnover and suppressing the expression of molecules involved in melanin production. In this study, we found that the expression of iron metabolism-related genes is altered in the lower epidermis of pigmented spots, suppressing iron utilization. For example, we found that TFRC1, ACO1, SLC25A37, and DMT1 are down-regulated in the lower epidermis of pigmented spots. We believe that this mineral metabolism disorder leads to abnormal epidermal turnover, resulting in the lack of melanin excretion and the formation of pigmented spots.

[0011] Therefore, we thought that if we could find a component that would normalize the expression of molecules related to iron metabolism, in other words, promote iron utilization in the lower epidermis, we could restore normal epidermal cell proliferation and melanin turnover, thereby preventing and improving age spots. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Kawabata, H. (2010) Journal of the Japanese Society of Cardiology 99:1173-1179. [Non-patent document 2] Inoue Y et al(2014)J Biol chem., 1;289(31):21451-62. [Non-patent document 3] Asano MD et al(2017)J Dermatol Sci.,87(2):101-9. [Non-patent document 4] Iwai, K. et al. (2007) Biochemistry, Vol. 79, No. 11, 1021-31 [Non-Patent Document 5] Hideo Harigae (2013) Journal of the Japan Society of Internal Medicine 102:2699-2704 Summary of the Invention [Problem to be solved by the invention]

[0013] The object of the present invention is to provide a material that can prevent and improve pigmentation by improving mineral metabolic abnormalities in the lower part of the epidermis and normalizing epidermal cell proliferation and epidermal turnover. [Means for solving the problem]

[0014] After extensive research, the inventors discovered that certain components, such as Rehmannia glutinosa and Rehmannia glutinosa, have the effect of regulating the production of proteins involved in iron uptake, excretion, etc. in cells in the lower part of the epidermis, thereby promoting iron utilization.

[0015] That is, the present invention is (1) An agent for inhibiting mineral metabolism abnormalities in the lower epidermis of skin blemishes, comprising at least one active ingredient selected from the group consisting of Chinese laurel, Scutellaria root, olive leaf, honeysuckle, starfruit leaf, Centella asiatica, rose, artichoke, chamomilla, perilla, meadowsweet, peony, hamamelis, bilberry leaf, saxifrage, indigo, ginger, Houttuynia cordata, St. John's wort, spruce, kiwi, dead nettle, safflower, peach kernel, lychee, aloe, inositol, niacinamide, dipotassium glycyrrhizinate, oryzanol, tocopherol acetate, and tranexamic acid; (2) A mineral metabolism disorder inhibitor according to (1), which is based on the TFRC1 production-promoting effect and contains at least one active ingredient selected from the group consisting of Chinese laurel, Scutellaria root, olive leaf, honeysuckle, starfruit leaf, Centella asiatica, rose, artichoke, chamomilla recutita, perilla, meadowsweet, peony, witch hazel, bilberry leaf, saxifrage, indigo, ginger, Houttuynia cordata, tocopherol acetate, and tranexamic acid; (3) A mineral metabolism disorder inhibitor according to (1), wherein the active ingredient is at least one selected from the group consisting of star fruit leaf, inositol, niacinamide, dipotassium glycyrrhizinate, and oryzanol, and the inhibitor is based on the ACO1 production promoting effect. (4) A mineral metabolism disorder inhibitor according to (1), wherein the active ingredient is at least one selected from the group consisting of St. John's wort, spruce, kiwi, dead nettle, safflower, peach kernel, and lychee, and is based on an inhibitory effect on SLC40A1 production; (5) The mineral metabolism disorder inhibitor according to (1), wherein the active ingredient is at least one selected from the group consisting of honeysuckle and tocopherol acetate, and the inhibitor is based on the DMT1 production promoting effect. (6) The mineral metabolism disorder inhibitor according to (1), wherein the active ingredient is aloe and is based on the SLC25A37 production promoting effect. (7) A TFRC1 production promoter containing at least one active ingredient selected from the group consisting of Chinese laurel, Scutellaria root, olive leaf, honeysuckle, starfruit leaf, Centella asiatica, rose, artichoke, chamomilla recutita, perilla, meadowsweet, peony, witch hazel, bilberry leaf, saxifrage, indigo, ginger, Houttuynia cordata, tocopherol acetate, and tranexamic acid; (8) An ACO1 production promoter containing at least one active ingredient selected from the group consisting of star fruit leaf, inositol, niacinamide, dipotassium glycyrrhizinate, and oryzanol; (9) An SLC40A1 production inhibitor containing at least one active ingredient selected from the group consisting of St. John's wort, spruce, kiwi, dead nettle, safflower, peach kernel, and lychee. (10) A DMT1 production promoter containing at least one active ingredient selected from the group consisting of honeysuckle and tocopherol acetate. (11) An SLC25A37 production promoter containing aloe as an active ingredient. (12) A method for screening for agents for preventing or improving spots, using as an indicator the expression level of one or more genes selected from the group consisting of the TFRC1 gene, the ACO1 gene, the SLC40A1 gene, the DMT1 gene, and the SLC25A37 gene when a test substance is applied to undifferentiated human epidermal keratinocytes. [Effects of the Invention]

[0016] The mineral metabolism disorder inhibitor of the present invention regulates the production of proteins involved in mineral utilization, such as TFRC1, ACO1, SLC40A1, DMT1, and SLC25A37, thereby promoting iron utilization in cells in the lower epidermis and normalizing epidermal cell proliferation and epidermal turnover, thereby preventing and improving pigmentation. Furthermore, by promoting TFRC1 production, promoting ACO1 production, or inhibiting SLC40A1 production, promoting DMT1 production, and promoting SLC25A37 production, it can provide therapeutic and ameliorative effects for various symptoms and diseases caused by excess or decreased expression of these proteins. Furthermore, it can also be used as a positive control when screening for materials involved in the expression of these proteins or the genes encoding them. Furthermore, the screening method of the present invention allows efficient screening of ingredients that can prevent and improve pigmentation. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 is a graph showing the ΔΔCt values ​​of the TFRC1 gene in Test Example 1. [Figure 2] FIG. 2 is a graph showing the ΔΔCt values ​​of the ACO1 gene in Test Example 1. [Figure 3] FIG. 3 is a graph showing the ΔΔCt values ​​of the SLC40A1 gene in Test Example 1. [Figure 4] FIG. 4 is a graph showing the ΔΔCt values ​​of the DMT1 gene in Test Example 1. [Figure 5] FIG. 5 is a graph showing the ΔΔCt values ​​of the SLC25A37 gene in Test Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0018] In the present invention, the following ingredients are used as active ingredients.

[0019] The rosehip used in the present invention is a herb or plant derived from the fruit of Rosa multiflora Thunberg or other related plants (Rosaceae), and is used in the form of a herb powder or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0020] The Zoysia extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, polyhydric alcohols, or mixtures of these is most preferred.

[0021] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available rhododendron extracts include "rhododendron extract-R," "rhododendron extract BG-R," and "rhododendron extract BG-01" manufactured by Maruzen Pharmaceutical Co., Ltd., and "Falcorex (registered trademark) rhododendron B" manufactured by Ichimaru Falcos (registered trademark).

[0022] The Scutellaria root used in the present invention is a herb or plant derived from the root of Scutellaria baicalensis Georgi (Labiatae) of the family Lamiaceae, with the periderm removed, and is used in the form of a herb powder or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0023] The Rehmannia root extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, polyhydric alcohols, or mixtures of these is most preferred.

[0024] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available Scutellaria root extract products include Maruzen Pharmaceutical's "Scutellaria root extract liquid-J," and Ichimaru Falcos' "Scutellaria root extract powder," "Scutellaria root liquid B," "Scutellaria root liquid G," and "Scutellaria root liquid SE."

[0025] The olive leaves used in the present invention are herbal medicines or plants derived from the leaves of the olive tree Olea europaea, which belongs to the family Oleaceae, Lamiales, and are used in the form of herbal medicine powder or plant powder, herbal medicine extract or plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0026] The olive leaf extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or a mixture of these solvents.

[0027] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available olive leaf extracts include "Olive Leaf Extract BG" by Maruzen Pharmaceuticals.

[0028] The honeysuckle used in the present invention is a herbal medicine or plant derived from the flowers, leaves, or stems of Lonicera japonica Thunberg or other plants of the same genus (Caprifoliaceae) in the family Caprifoliaceae of the order Dipsacales, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0029] The honeysuckle extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0030] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available honeysuckle extracts include "Honeysuckle Extract-J" from Maruzen Pharmaceuticals, and "Falcorex Honeysuckle FB" and "Falcorex Honeysuckle FE" from Ichimaru Falcos.

[0031] The star fruit leaves used in the present invention are a herbal medicine or plant derived from the leaves of Averrhoa carambola, which belongs to the Oxalidaceae family and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0032] The star fruit leaf extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or a mixture of these solvents.

[0033] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available star fruit leaf extract products include "Star Fruit Leaf Extract Liquid BG30" and "Star Fruit Leaf Extract Powder MF" manufactured by Maruzen Pharmaceuticals.

[0034] The Centella used in the present invention is a herbal medicine or plant derived from the leaves and stems of Centella asiatica Linne (Umbelliferae), which belongs to the Apiales, Umbelliferae, and genus Centella, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0035] The Centella asiatica extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0036] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available Centella asiatica extracts include "Centella asiatica extract BG70" manufactured by Maruzen Pharmaceuticals.

[0037] The rose used in the present invention is a herbal medicine or plant derived from the flower of the European rose, Rosa centifolia Linne (Rosaceae), which belongs to the family Rosaceae, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0038] The rose extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of these solvents. Of these, extraction with water, a polyhydric alcohol, or a mixture of these is most preferred.

[0039] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available rose extract products include Maruzen Pharmaceutical's "Rose Extract BG," and Ichimaru Falcos' "Falcolex Rose P," "Rose Water," and "Rose Water PF."

[0040] The artichoke used in the present invention is a herbal medicine or plant derived from the leaves of Cynara scolymus Linne (Compositae), a member of the Asteraceae family, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0041] The artichoke extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or a mixture of these solvents.

[0042] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available artichoke extract products include Ichimaru Falcos' BioBenefity (registered trademark), BioBenefity G, BioBenefity HS, Cynaropicrin F, and BioBenefity F.

[0043] The chamomilla used in the present invention is a herbal medicine or plant derived from the flowers of Matricaria chamomilla Linne (Compositae), a member of the Asteraceae family, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0044] The chamomilla extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of these solvents, or a mixture of these solvents containing urea. Of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these, or a mixture of these with urea is most preferred.

[0045] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available chamomilla extract products include Maruzen Pharmaceutical's "Chamomile Extract," "Chamomile Extract BG-J," and "Chamomile Extract LA," and Ichimaru Falcos' "Eau de Aroma (registered trademark) Chamomile," "Eau de Aroma Chamomile B," "Chamomile Liquid," and "Biocellact (registered trademark) Chamomile B."

[0046] The perilla used in the present invention is a herb or plant derived from the leaves and branch tips of Perilla frutescens Britton Var. acuta Kudo, or other related species of the Labiatae family, and is used in the form of a herb powder or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, chopped product that has been further finely pulverized into a powder.

[0047] The perilla extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of these solvents. Of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0048] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available perilla extract products include "Perilla Extract BG" and "Green Perilla Extract MF(N)" from Maruzen Pharmaceutical, and "Falcorex Perilla" and "Falcorex Perilla HB" from Ichimaru Falcos.

[0049] The meadowsweet used in the present invention is a herb or plant derived from the inflorescence of Filipendula ulmaria Maximowicz (Rosaceae), a member of the genus Meadowsweet, belonging to the family Rosaceae, and is used in the form of a herb or plant powder, a herb or plant extract, or a plant extract. The herb or plant powder used in the present invention may be, for example, a dried, chopped product further finely pulverized into a powder.

[0050] The meadowsweet extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or mixtures of the above solvents, but extraction with water, polyhydric alcohols, or mixtures of these is most preferred.

[0051] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available meadowsweet extracts include "Falcorex Meadowsweet B" by Ichimaru Falcos.

[0052] The peony used in the present invention is a herbal medicine or plant derived from the root of Paeonia lactiflora Pallas (Paeonia albiflora Pallas var. trichocarpa Bunge) or other related plants (Paeoniaceae) of the family Paeoniaceae, order Saxifragales, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further finely pulverized into a powder.

[0053] The peony extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0054] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available peony extracts include "Peony Extract-J," "Peony Extract BG-JC," and "Waism (registered trademark) Peony" from Maruzen Pharmaceuticals, and "Peony Liquid" and "Falcorex Peony B" from Ichimaru Falcos.

[0055] The witch hazel used in the present invention is a herbal medicine or plant derived from the leaves or leaves and bark of Hamamelis virginiana L. (Hamamelidaceae), which belongs to the Hamamelidaceae family of the Saxifragales order, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, powdered product obtained by further finely pulverizing a dried, chopped product.

[0056] The witch hazel extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0057] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available products of witch hazel extract include "Witch Hazel Extract BG-J" by Maruzen Pharmaceuticals and "Falcorex Witch Hazel B" by Ichimaru Falcos.

[0058] The bilberry leaves used in the present invention are a herbal medicine or plant derived from the leaves of Vaccinium myrtillus L. (Ericaceae), which belongs to the Ericaceae family of the Ericales order, and are used in the form of a herbal medicine powder or plant powder, a herbal medicine extract or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, powdered product obtained by further finely pulverizing a dried, chopped product.

[0059] The bilberry leaf extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), or lower aliphatic ketones (e.g., acetone), or a mixture of these solvents.

[0060] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available bilberry leaf extract products include Ichimaru Falcos' "Ecofarm (registered trademark) Bilberry Leaf E," "Ecofarm Bilberry Leaf G," and "Cureberry (registered trademark)."

[0061] The saxifragaceae used in the present invention is a crude drug or plant derived from the whole plant of Saxifraga stolonifera Meerburg (Saxifragaceae), which belongs to the family Saxifragaceae, and is used in the form of a crude drug powder or plant powder, a crude drug extract, or a plant extract. The crude drug powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0062] The saxifrage extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, polyhydric alcohols, or mixtures of these is most preferred.

[0063] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available saxifrage extracts include Maruzen Pharmaceutical's "Saxifrage Extract Liquid," "Saxifrage Extract Liquid BG," and "Waism <Saxifrage>," and Ichimaru Falcos' "Falcorex Saxifrage MB."

[0064] The indigo used in the present invention is a herbal medicine or plant derived from the leaves / stem of Polygonum tinctorium Lour. (Polygonaceae), and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0065] The indigo extract used in the present invention can be extracted using solvents such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or mixtures of the above solvents.

[0066] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available indigo extract products include "Ai Luros (registered trademark)" by Ichimaru Falcos.

[0067] The ginger used in the present invention is a herbal medicine or plant derived from the rhizome of Zingiber officinale Roscoe (Zingiberaceae), which belongs to the family Zingiberaceae, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0068] The ginger extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, or mixtures thereof is most preferred.

[0069] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available ginger extract products include "Ginger Tincture" from Maruzen Pharmaceuticals and "Falcorex Ginger E" from Ichimaru Falcos.

[0070] The Houttuynia cordata used in the present invention is a herbal medicine or plant derived from the aerial parts of the flowering genus Houttuynia, Houttuynia cordata Thunberg (Saururaceae), belonging to the family Houttuyniaceae, order Piperaceae, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further finely pulverized into a powder.

[0071] The Houttuynia cordata extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, polyhydric alcohols, or mixtures of these is most preferred.

[0072] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available Houttuynia cordata extracts include Maruzen Pharmaceutical's "Houttuynia Cordata Extract Liquid," "Houttuynia Cordata Extract Liquid BG," and "Houttuynia Cordata Extract Powder MF," and Ichimaru Falcos's "Falcorex Houttuynia Cordata B," "Falcorex Houttuynia Cordata E," "Falcorex Houttuynia Cordata W," and "Houttuynia Cordata DXP100."

[0073] The St. John's wort used in the present invention is a herb or plant derived from the aerial parts of Hypericum perforatum Linne or Hypericum erectum Thunberg (Guttiferae) of the family Hypericaceae of the orders Cantharaneales, and is used in the form of a herb powder or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, chopped product further finely pulverized into a powder.

[0074] The St. John's wort extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0075] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available products of St. John's Wort extract include "St. John's Wort Extract BG" from Maruzen Pharmaceutical, and "Falcorex St. John's Wort B" and "Falcorex St. John's Wort E" from Ichimaru Falcos.

[0076] The spruce used in the present invention is a herb or plant derived from the mature pericarp of Citrus aurantium Linne or Citrus aurantium Linne var. daidai Makino (Rutaceae), which belongs to the family Pinaceae, order Pinales, and is used in the form of a herb powder or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0077] The spruce extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (methanol, ethanol, isopropyl alcohol, etc.), a polyhydric alcohol (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), a lower aliphatic ketone (acetone, etc.), or a mixture of these solvents, but it is most preferred to extract with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these.

[0078] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available spruce extract products include "Spruce Extract (Glaurel Salt)" from Maruzen Pharmaceuticals, and "Spruce Liquid" and "Spruce Liquid B" from Ichimaru Falcos.

[0079] The kiwi fruit used in the present invention is a herbal medicine or plant derived from the fresh fruit of Actinidia chinensis Planch (Actinidiaceae), a member of the Actinidiaceae family in the Theales order, and is used in the form of a powdered herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The powdered herbal medicine or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0080] The kiwi extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or mixtures of the above solvents, but extraction with water is most preferred.

[0081] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available kiwi extract products include "Falcorex Kiwi" and "Falcorex Kiwi B" from Ichimaru Falcos.

[0082] The dead nettle used in the present invention is a herbal medicine or plant derived from the flowers, stems, or leaves of the genus Lamium, Lamium album Linne (Labiatae), family Lamiaceae, order Lamiales, and is used in the form of a powdered herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The powdered herbal medicine or plant powder used in the present invention may be, for example, a dried, shredded product further finely pulverized into a powder.

[0083] The white lamb extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a polyhydric alcohol, or a mixture of these is most preferred.

[0084] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available products of dead nettle extract include "Falcorex Dead Nettle B" by Ichimaru Falcos.

[0085] The safflower used in the present invention is a herb or plant derived from the flowers of Carthamus tinctorius Linne (Compositae) of the genus Carthamus in the family Asteraceae, order Asterales, either as is or after most of the yellow pigment has been removed and compressed into sheets, and is used in the form of a herb powder or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, chopped product that has been further finely pulverized into a powder.

[0086] The safflower extract used in the present invention can be extracted using solvents such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or mixtures of the above solvents, but extraction using water, lower aliphatic alcohols, polyhydric alcohols, or mixtures of these is most preferred.

[0087] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available safflower extract products include "Safflower Extract" and "Safflower Extract BG" from Maruzen Pharmaceuticals, and "Falcorex Safflower B" and "Safflower Liquid" from Ichimaru Falcos.

[0088] The peach kernel used in the present invention is a herb or plant derived from the seeds of Prunus persica Batsch or Prunus persica Batsch var. davodoana Maximowicz (Rosaceae), a species of the peach genus in the family Rosaceae, and is used in the form of a herb powder or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, chopped product further finely pulverized into a powder.

[0089] The peach extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, polyhydric alcohols, or mixtures of these is most preferred.

[0090] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available tonic extracts include "Tonic Extract-J" from Maruzen Pharmaceuticals and "Falcorex Tonic B" from Ichimaru Falcos.

[0091] The lychee used in the present invention is a herbal medicine or plant derived from the fruit of Litchi chinensis Sonn. (Sapindaceae), which belongs to the family Sapindaceae, order Sapindales, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, powdered product obtained by further finely pulverizing a dried, chopped product.

[0092] The lychee extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or a mixture of these solvents.

[0093] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available lychee extract products include Ichimaru Falcos' "ADS-Oligonol" and "Oligonol-CS."

[0094] The aloe used in the present invention is a herb or plant derived from the leaves or leaf sap of Aloe Ferox Miller, a hybrid of Aloe Ferox Miller with Aloe Africana Miller or Aloe spicata Baker (Liliaceae), belonging to the Asparagaceae family, or Aloe barbadensis Miller (Aloe vera Linne), or Aloe arborescens Miller and its varieties (Liliaceae), and is used in the form of a herb powder, plant powder, herb extract, or plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, chopped product further finely pulverized into a powder.

[0095] The aloe extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of these solvents. Of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0096] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, or vacuum drying. Examples of commercially available extracts include: Commercially available aloe extracts include Ichimaru Falcos' "Arrow Cave Liquid" and "Arrow Cave Liquid B-7(N)."

[0097] Inositol used in the present invention is a general term for cyclohexane hexahydric alcohol and is a water-soluble vitamin-like substance. Niacinamide is a compound specified by Cas No. 98-92-0, dipotassium glycyrrhizinate by Cas No. 68797-35-3, tocopherol acetate by Cas No. 7695-91-2, and tranexamic acid by Cas No. 1197-18-8. Oryzanol is obtained from the seeds of rice (Oryza sativa Linne (Gramineae)) and is a general term for esters mainly consisting of esters of triterpene alcohols and ferulic acid.

[0098] Skin is broadly divided into three layers: the epidermis, dermis, and subcutaneous tissue. The main constituent cells of the epidermis are keratinocytes, which undergo four stages of morphological change during differentiation. Basal cells in the lowest layer contact the basement membrane, synthesize DNA, and divide and proliferate. These divided cells migrate upward and become spinous cells. Further differentiation leads to granular cells, which ultimately differentiate into corneocytes, forming the stratum corneum (stratum corneum). Keratinocytes at these stages of differentiation are layered within the epidermis. The stratum corneum's keratinocytes are adhered to each other by desmosomes. However, in healthy skin, this adhesion mechanism gradually weakens, leading to spontaneous detachment of the stratum corneum in response to physical stimuli (stratum corneum desquamation). In this way, the epidermis undergoes a rhythmic cycle of proliferation, differentiation, and exfoliation (epidermal turnover). In addition to keratinocytes, melanocytes exist in the epidermis and produce melanin. Normally, melanin is transferred to keratinocytes and excreted with the stratum corneum peeling during epidermal turnover. However, if abnormalities in epidermal turnover occur, such as a decrease in differentiation and proliferation from basal cells or excessive proliferation of keratinocytes, resulting in stratification and thickening, melanin is not excreted and accumulates in the epidermis, resulting in the formation of age spots. In this specification, the lower epidermis refers to the layer containing basal cells among the keratinocytes that make up the epidermis, and the upper epidermis refers to the layer containing keratinocytes.

[0099] Transferrin receptor 1 (TFRC1) is expressed in various cells in the body, and after serum iron binds to transferrin and is transported, the iron is taken up into cells via TFRC1. When cells are iron deficient, TFRC1 expression decreases, indicating that TFRC1 plays an important role in the uptake of iron into cells. When TFRC1 production is promoted in keratinocytes in the lower epidermis, the uptake of iron into cells is promoted, increasing the intracellular iron concentration, promoting epidermal turnover and epidermal layer regeneration, and promoting the excretion of melanin pigment, thereby preventing and / or improving pigmentation (Non-Patent Documents 1 and 3).

[0100] Among the above active ingredients, star fruit, Chinese laurel, olive leaf, honeysuckle, star fruit leaf, Centella asiatica, rose, artichoke, chamomilla, perilla, meadowsweet, peony, witch hazel, bilberry leaf, saxifrage, indigo, ginger, houttuynia cordata, tocopherol acetate, and tranexamic acid have the effect of promoting TFRC1 production in the lower epidermis.

[0101] ACO1 functions as an essential enzyme in the TCA cycle, catalyzing the reaction from citrate to aconitate and then isocitrate. When intracellular iron concentrations are high, this protein functions as aconitase. When intracellular iron concentrations are low, the protein binds to the iron response element (IRE). When ACO1 production is promoted in keratinocytes in the lower epidermis, it not only activates mitochondria in basal cells, but also normalizes iron utilization by stabilizing intracellular iron concentrations, promoting epidermal turnover and melanin excretion, thereby preventing and / or improving pigmentation (Non-Patent Document 4).

[0102] Among the above active ingredients, star fruit leaf, inositol, niacinamide, dipotassium glycyrrhizinate, and oryzanol have the effect of promoting ACO1 production.

[0103] SLC40A1 (ferroportin) is responsible for the excretion of iron from cells. Ferroportin expression is regulated according to intracellular iron deficiency and by hepcidin at the protein level according to iron deficiency at the individual level. Ferroportin is known to be a protein that excretes iron from intestinal epithelial cells and macrophages into the bloodstream, but in recent years, it has been reported that it is also expressed in skin tissue. Suppression of SLC40A1 production in keratinocytes in the lower epidermis suppresses the decrease in intracellular iron concentration in keratinocytes, thereby normalizing cell proliferation and epidermal turnover, resulting in the prevention and / or improvement of pigmentation (Non-Patent Documents 1, 3, 5).

[0104] Among the above active ingredients, St. John's wort, spruce, kiwi, dead nettle, safflower, peach kernel, and lychee have the effect of inhibiting SLC40A1 production.

[0105] DMT1, a divalent metal transporter, is responsible for iron uptake from the intestinal tract and iron transport from endosomes. DMT1 binds various divalent metals, including cadmium (Cd 2+ ), copper (Cu 2+ ), and zinc (Zn 2+ ), but is best known for its role in iron (Fe 2+ ) transport. DMT1 expression is regulated by the body's iron stores to maintain iron homeostasis. In the gastrointestinal tract, it is located on the apical membrane of enterocytes and is known to bind and transport divalent metal cations from the intestinal lumen into the cells. Recently, it has been reported that DMT1 is also expressed in the epidermis of skin tissue. Enhanced DMT1 production in keratinocytes in the lower epidermis promotes intracellular iron uptake, increases intracellular iron concentration, and normalizes epidermal turnover and epidermal layer regeneration, resulting in the prevention and / or improvement of pigmentation.

[0106] Among the above active ingredients, honeysuckle and tocopherol acetate have the effect of promoting DMT1 production.

[0107] Mitochondria are the main intracellular organelles that utilize iron, and SLC25A37 (Mitoferrin 1) functions as an iron uptake transporter in the inner mitochondrial membrane. It exists as a key molecule in iron metabolism in intracellular mitochondria. When SLC25A37 production is promoted in keratinocytes in the lower epidermis, it promotes iron transport to intracellular mitochondria, thereby increasing intracellular iron concentration and normalizing epidermal turnover and epidermal layer regeneration, thereby preventing and / or improving pigmentation (Non-Patent Document 5).

[0108] Among the above active ingredients, aloe has the effect of promoting SLC25A37 production.

[0109] As described above, the present invention provides a TFRC1 production promoting effect by at least one selected from the group consisting of star fruit leaf, inositol, niacinamide, dipotassium glycyrrhizinate, and oryzanol; and a TFRC1 production promoting effect by at least one selected from the group consisting of star fruit leaf, inositol, niacinamide, dipotassium glycyrrhizinate, and oryzanol; and a TFRC1 production promoting effect by at least one selected from the group consisting of star fruit leaf, inositol, niacinamide, dipotassium glycyrrhizinate, and oryzanol; and a TFRC1 production promoting effect by at least one selected from the group consisting of star fruit leaf, inositol, niacinamide, dipotassium glycyrrhizinate, kiwi fruit, white dead nettle, safflower, peach kernel, and lye. The active ingredients in this product include an inhibitor of mineral metabolism abnormalities in the lower epidermis of skin blemishes based on the inhibitory effect of SLC40A1 production by at least one selected from the group consisting of honeysuckle and tocopherol acetate, the promotion of DMT1 production by at least one selected from the group consisting of honeysuckle and tocopherol acetate, and the promotion of SLC25A37 production by aloe, as well as a TFRC1 production promoter, ACO1 production promoter, SLC40A1 production inhibitor, DMT1 production promoter, and SLC25A37 production promoter based on the above active ingredients, and further have the effect of preventing and improving diseases and symptoms caused by a decrease in TFRC1, a decrease in ACO1, an excess of SLC40A1, a decrease in DMT1, and a decrease in SLC25A37.

[0110] The mineral metabolism disorder inhibitor, TFRC1 production promoter, ACO1 production promoter, SLC40A1 production inhibitor, DMT1 production promoter, and SLC25A37 production promoter of the present invention can be provided as cosmetics, quasi-drugs, pharmaceuticals, foods and beverages, etc. Although they are preferably applied to humans, they can also be applied to animals other than humans as long as the functional effects are achieved.

[0111] The mineral metabolism disorder inhibitors, TFRC1 production promoters, ACO1 production promoters, SLC40A1 production inhibitors, DMT1 production promoters, and SLC25A37 production promoters of the present invention can be used, for example, for research into related symptoms or diseases, or for normalizing mineral metabolism disorders at the site of pigmentation, or as reagents for promoting TFRC1 production, promoting ACO1 production, suppressing SLC40A1 production, promoting DMT1 production, or promoting SLC25A37 production, and are preferably used as positive control agents when conducting material screening, etc. The present invention includes methods for promoting TFRC1 production, ACO1 production, DMT1 production, and SLC25A37 production, as well as methods for suppressing SLC40A1 production, in such tests and studies. Methods for promoting TFRC1 production include adding witch hazel, ginger, rose, saxifrage, star fruit, honeysuckle, artichoke, indigo, meadowsweet, star fruit leaf, peony, bilberry leaf, chamomilla recutita, scutellaria, houttuynia cordata, perilla, olive leaf, Centella asiatica, tocopherol acetate, tranexamic acid, or an extract of each to epidermal keratinocytes or cells in which TFRC1 production is desired to be promoted. Methods for promoting ACO1 production include adding star fruit leaf, inositol, niacinamide, dipotassium glycyrrhizinate, oryzanol, or an extract thereof to epidermal keratinocytes or cells in which ACO1 production is desired to be promoted. Methods for promoting DMT1 production include adding honeysuckle, tocopherol acetate, or an extract of each to epidermal keratinocytes or cells in which DMT1 production is desired to be promoted. A method for promoting SLC25A37 production includes adding aloe or an extract thereof to epidermal keratinocytes or cells in which SLC25A37 production is desired to be promoted. A method for suppressing SLC40A1 production includes adding St. John's wort, spruce, kiwi, dead nettle, safflower, peach kernel, lychee, or an extract of each of these to epidermal keratinocytes or cells in which SLC40A1 promotion is desired to be suppressed.

[0112] The dosage form is not particularly limited, but oral administration is preferred. Dosage forms for oral administration include tablets, powders, powders, granules, liquids, capsules, dry syrups, jellies, liquid foods, semi-solid foods, and solid foods. These can be produced by known methods. During production, various additives that can be contained in quasi-drugs, pharmaceuticals, foods and beverages, or reagents can be blended within a range that does not impair the effects of the present invention.

[0113] The amount of the active ingredient in the present invention is not particularly limited, but when provided as a cosmetic, quasi-drug, pharmaceutical, food or beverage, or reagent, it is 0.000001 to 10% by mass, preferably 0.0001 to 5% by mass, and more preferably 0.001 to 1% by mass, based on the total mass of the composition.

[0114] The mineral metabolism disorder inhibitors, TFRC1 production promoters, ACO1 production promoters, SLC40A1 production inhibitors, DMT1 production promoters, and SLC25A37 production promoters of the present invention (such as pharmaceuticals, quasi-drugs, foods and beverages, and reagents) and their instructions may be labeled with a label indicating that the product is used for promoting TFRC1 production, a label indicating that the product is used for promoting ACO1 production, a label indicating that the product is used for inhibiting SLC40A1 production, a label indicating that the product is used for promoting DMT1 production, or a label indicating that the product is used for promoting SLC25A37 production. Here, "labeled" includes a label indicating that the product is used on the body, container, packaging, etc. of the product containing the mineral metabolism disorder inhibitor, TFRC1 production promoter, ACO1 production promoter, SLC40A1 production inhibitor, DMT1 production promoter, or SLC25A37 production promoter, or in documents such as product information instructions, package inserts, pamphlets, and other printed materials, as well as in various flyers and advertisements used for promotion, including online advertising.

[0115] The screening method of the present invention uses undifferentiated human epidermal keratinocytes. The medium used for cell culture is not particularly limited, and known mediums can be used, and the cells can be cultured under standard culture conditions. A test substance is added to the medium containing the cultured undifferentiated human epidermal keratinocytes. After culturing for a predetermined period of time, the expression levels of one or more genes selected from the group consisting of TFRC1, ACO1, SLC40A1, DMT1, and SLC25A37 are measured. The gene expression levels are not particularly limited, and known methods can be used. An untreated group, to which no test substance has been added, is similarly cultured, and the expression levels of each gene are measured. By comparing the gene expression levels with those of the test substance-treated group, the presence or absence of the test substance's effect on preventing or improving age spots can be determined. Furthermore, because the expression levels of TFCR1, DMT1, and SLC40A1 (ferroportin) are reduced in the lower epidermis in areas with pigmentation, the presence or absence of a test substance's pigmentation prevention or improvement effects can be determined by comparing the gene expression levels of these genes in a pigmentation pathology model with the gene expression levels observed when a test substance is added. Similar tests can also be performed using differentiated human epidermal keratinocytes to select test substances that increase TFCR1 expression in undifferentiated cells but do not increase TFCR1 expression in differentiated cells. By combining indicators of changes in gene expression specific to pigmentation pathology, it is possible to select ingredients with superior pigmentation prevention and improvement effects. [Example]

[0116] The present invention will be explained in more detail below with reference to examples and test examples, but the present invention is not limited to these examples.

[0117] (Test Example 1) Evaluation of gene expression promotion or inhibition in undifferentiated human epidermal keratinocytes <Test Method> Human epidermal keratinocytes (Kurashiki Boseki) were placed in a 12-well plate at 3.8 × 10 4Cells were seeded at a density of 1000 cells / well and cultured in an incubator set at 37°C and 5% CO2. Humedia-KG2 (Kurashiki Boseki) medium was used. The day after seeding, the medium was replaced with test substance-supplemented medium and cultured in a CO2 incubator for 1 day. Cells were then lysed by adding lysate buffer, and the cell lysate was collected. RNA was extracted from the cell lysate using an RNeasy Mini Kit (Qiagen) according to the attached protocol. Using this as a template, cDNA was synthesized by reverse transcription using Prime Script RT Master mix (Takara Bio). The mRNA expression levels of RPLP0, TFRC1, ACO1, SLC40A1, DMT1, and SLC25A37 were measured using a real-time PCR system (Step One Plus, Thermo Fisher Scientific) using the SYBR Green method. The ΔCt value was calculated by subtracting the Ct value of the internal control gene RPLP0 from the Ct value of each sample for TFRC1, ACO1, SLC40A1, DMT1, and SLC25A37. Furthermore, the ΔCt value was calculated by subtracting the ΔCt value of the untreated sample from the ΔCt value of the test substance-treated sample. For example, a ΔΔCt value of -1 indicates a 2-fold change in gene expression, and a value of 1 indicates a 1 / 2-fold change. The primers used were those with the following sequences or product numbers: RPLP0: (F) 5'-GAAGCCACGCTGCTGAACA-3' (R) 5'-CTGGCAACATTGCGGACA-3', SLC25A37: (F) 5'-GAAGCAGCAGTACATTTGTCATTCA-3' (R) 5'-CTGGCAACATTGCGGACA-3' (primer synthesis), TFRC1: HA277353, ACO1: HA210761, SLC40A1: HA161921, DMT1: HA142595 (Takara Bio). All test substances were used at a final concentration of 1%, except for lychee (0.01%), inositol (2%), niacinamide (0.05%), dipotassium glycyrrhizinate (0.1%), oryzanol (0.005%), and tranexamic acid (2%). Tocopherol acetate was used at a final concentration of 0.1% and 1%. The untreated group was cultured in medium without the addition of the test substance, and all other conditions were the same as those in the test substance-added group.

[0118] <Test Results> Figure 1 is a graph showing the ΔΔCt values ​​of the TFRC1 gene. Compared to the untreated group, the treatments of Chinese laurel, Scutellaria root, olive leaf, honeysuckle, starfruit leaf, Centella asiatica, rose, artichoke, chamomilla recutita, perilla, meadowsweet, peony, hamamelis virginiana, bilberry leaf, saxifrage, indigo, ginger, Houttuynia cordata, tocopheryl acetate (1%), and tranexamic acid increased TFRC1 gene expression. Figure 2 is a graph showing the ΔΔCt values ​​of the ACO1 gene. Compared to the untreated group, star fruit leaf, inositol, niacinamide, dipotassium glycyrrhizinate, and oryzanol increased ACO1 gene expression. Figure 3 is a graph showing the ΔΔCt values ​​of the SLC40A1 gene. Compared to the untreated group, Hypericum perforatum, dead nettle, kiwi, peach kernel, spruce, lychee, and safflower reduced SLC40A1 gene expression. 4 is a graph showing the ΔΔCt values ​​of the DMT1 gene. Compared to the untreated group, honeysuckle and tocopherol acetate (0.1%) increased DMT1 gene expression. 5 is a graph showing the ΔΔCt values ​​of the SLC25A37 gene. Compared to the untreated group, aloe vera increased SLC25A37 gene expression. [Industrial Applicability]

[0119] The agent for inhibiting mineral metabolism abnormalities in the lower epidermis of pigmented spots of the present invention has the effect of preventing and improving pigmented spots based on its actions of promoting TFRC1 production, promoting ACO1 production, inhibiting SLC40A1 production, promoting DMT1 production, and promoting SLC25A37 production, and can therefore be used in the fields of quasi-drugs, pharmaceuticals, and foods and beverages. Furthermore, the TFRC1 production promoter, ACO1 production promoter, SLC40A1 production inhibitor, DMT1 production promoter, and SLC25A37 production promoter of the present invention can be used as a positive control drug when conducting material screening, etc.

Claims

1. An agent containing tranexamic acid as its active ingredient that inhibits abnormal iron metabolism in the lower epidermis of skin blemishes.

2. The agent for suppressing abnormal iron metabolism according to claim 1, which is based on the effect of promoting TFRC1 production.

3. A TFRC1 production promoter containing tranexamic acid as an active ingredient.

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